Gip and glp-1 dual receptor agonist, pharmaceutical composition, and use

Abstract

A GIP and GLP-1 dual receptor agonist, a pharmaceutical composition, and the use. In particular, the present application relates to a compound represented by formula I, a pharmaceutical composition comprising the compound, and the use of the compound as a GIP and GLP-1 dual receptor agonist in the field of medicine. The compound represented by formula I exhibits excellent GIPR and GLP-1R agonist activity and excellent pharmaceutical activity in reducing blood sugar and controlling body weight, is a therapeutic drug having a clinical application prospect, and can be used for preventing and treating diseases such as diabetes, diabetes complications, obesity, or obesity complications.

1 . A compound represented by formula I or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled compound or prodrug thereof: 
       
         
           
                 
               
                   I 
                 
                   Tyr-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile- 
                 
                     
                 
                   Aib-Leu-Asp-Lys-Ile-Ala-Gln-Lys-Ala-Phe-Val-Gln- 
                 
                     
                 
                   Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro- 
                 
                     
                 
                   Pro-Pro-Ser-A 40 ; 
                 
             
                
                
                
                
                
                
                
                
               
            
           
         
         wherein, 
         A 40  is the following structure connecting to Ser via a peptide bond: 
       
       
         
           
           
               
               
           
         
         R 1  is —(Z 1 ) m —(Z 2 ) n —C(═O)—(CH 2 ) o —C(═O)—Z 3 ; 
         m is 0 or 1; 
         if present, Z 1  is —C(═O)—(CH 2 ) r —(Z 4 ) p —NH—, wherein p is any integer of 4-8, each Z 4  is independently —O—CH 2 —CH 2 — or —NH—C(═O)—CH 2 —, and r is 1 or 2; 
         n is any integer of 0-2; 
         if present, each Z 2  is independently 
       
       
         
           
           
               
               
           
         
       
       wherein q is any integer of 2-5;
 o is any integer of 14-18; 
 and Z 3  is hydroxyl or 
 
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled compound or prodrug thereof according to  claim 1 , wherein,
 R 1  is —C(═O)—(CH 2 ) o —C(═O)—Z 3 ;   o is any integer of 14-18, or o is 18;   and Z 3  is hydroxyl or   
       
         
           
           
               
               
           
         
       
       or Z 3  is hydroxyl. 
     
     
         3 . The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled compound or prodrug thereof according to  claim 1 , wherein,
 R 1  is —Z 1 —Z 2 —C(═O)—(CH 2 ) o —C(═O)—Z 3 ;   Z 1  is —C(═O)—CH 2 —(Z 4 ) 7 —NH—, wherein each Z 4  is independently —O—CH 2 —CH 2 — or —NH—C(═O)—CH 2 —, or wherein —(Z 4 ) 7 — is —(O—CH 2 —CH 2 ) 3 —(NH—C(═O)—CH 2 )—(O—CH 2 —CH 2 ) 3 — or —(O—CH 2 —CH 2 ) 7 —;   Z 2  is   
       
         
           
           
               
               
           
         
       
       or Z 2  is 
       
         
           
           
               
               
           
         
       
       wherein q is any integer of 2-5, or q is 2;
 o is any integer of 14-18, or o is 18; 
 and Z 3  is hydroxyl or 
 
       
         
           
           
               
               
           
         
       
       or Z 3  is hydroxyl. 
     
     
         4 . The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled compound or prodrug thereof according to  claim 1 , wherein, A 40  is selected from a structure represented by any one of the followings: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or A 40  is selected from a structure represented by any one of the followings: 
       
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound represented by any one of the following formulas I-1 o I-14 or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled compound or prodrug thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled compound or prodrug thereof according to  claim 1 ; wherein
 optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.   
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . A method for preventing and/or treating diseases associated with metabolic disorders, comprising administering a prophylactically and/or therapeutically effective amount of the compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled compound or prodrug thereof according to  claim 1  to a subject; wherein
 optionally, the diseases associated with metabolic disorders are diabetes, diabetes complications, obesity, or obesity complications. 
 
     
     
         11 . A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled compound or prodrug thereof according to  claim 5 ; wherein
 optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.   
     
     
         12 . A method for preventing and/or treating diseases associated with metabolic disorders, comprising administering a prophylactically and/or therapeutically effective amount of the compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopically labeled compound or prodrug thereof according to  claim 5  to a subject; wherein
 optionally, the diseases associated with metabolic disorders are diabetes, diabetes complications, obesity, or obesity complications. 
 
     
     
         13 . A pharmaceutical composition comprising the GIP and GLP-1 dual receptor agonist according to claim  6 ; wherein
 optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.   
     
     
         14 . A method for preventing and/or treating diseases associated with metabolic disorders, comprising administering a prophylactically and/or therapeutically effective amount of the GIP and GLP-1 dual receptor agonist according to claim  6  to a subject; wherein
 optionally, the diseases associated with metabolic disorders are diabetes, diabetes complications, obesity, or obesity complications. 
 
     
     
         15 . A method for preventing and/or treating diseases associated with metabolic disorders, comprising administering a prophylactically and/or therapeutically effective amount of the pharmaceutical composition according to  claim 7  to a subject; wherein
 optionally, the diseases associated with metabolic disorders are diabetes, diabetes complications, obesity, or obesity complications. 
 
     
     
         16 . A method for preventing and/or treating diseases associated with metabolic disorders, comprising administering a prophylactically and/or therapeutically effective amount of the pharmaceutical composition according to  claim 11  to a subject; wherein
 optionally, the diseases associated with metabolic disorders are diabetes, diabetes complications, obesity, or obesity complications. 
 
     
     
         17 . A method for preventing and/or treating diseases associated with metabolic disorders, comprising administering a prophylactically and/or therapeutically effective amount of the pharmaceutical composition according to  claim 13  to a subject; wherein
 optionally, the diseases associated with metabolic disorders are diabetes, diabetes complications, obesity, or obesity complications.